1. Voxel-Based Morphometry John Ashburner Wellcome Trust Centre for Neuroimaging, 12 Queen Square, London, UK.

2. Overview Voxel-Based Morphometry Morphometry in general Volumetrics VBM preprocessing followed by SPM Segmentation Dartel Recap

3. Measuring differences with MRI What are the significant differences between populations of subjects? What effects do various genes have on the brain? What changes occur in the brain through development or aging? A significant amount of the difference (measured with MRI) is anatomical. You need to discount the larger anatomical differences before giving explanations about brain function.

4. There are many ways to model differences. Usually, we try to localise regions of difference. Univariate models. Using methods similar to SPM Typically localising volumetric differences Some anatomical differences can not be localised. Need multivariate models. Differences in terms of proportions among measurements. Where would the difference between male and female faces be localised? Need to select the best model of difference to use, before trying to fill in the details.

5. Some 2D Shapes

6. Spatially normalised shapes

7. Deformations Could do a multivariate analysis of these (“Deformation-Based Morphometry”).

8. Relative Volumes Could do a mass-univariate analysis of these (“Tensor-Based Morphometry”).

9. Voxel-Based Morphometry Based on comparing regional volumes of tissue. Produce a map of statistically significant differences among populations of subjects. e.g. compare a patient group with a control group. or identify correlations with age, test-score etc. The data are pre-processed to sensitise the tests to regional tissue volumes. Usually grey or white matter. Suitable for studying focal volumetric differences of grey matter.

10. Volumetry T1-Weighted MRI Grey Matter

11. Original WarpedTemplate

12. “Modulation” – change of variables. Deformation FieldJacobians determinants Encode relative volumes.

13. Smoothing Before convolutionConvolved with a circleConvolved with a Gaussian Each voxel after smoothing effectively becomes the result of applying a weighted region of interest (ROI).

14. VBM Pre-processing in SPM8 Use New Segment for characterising intensity distributions of tissue classes, and writing out “imported” images that DARTEL can use. Run DARTEL to estimate all the deformations. DARTEL warping to generate smoothed, “modulated”, warped grey matter. Statistics.

15. Statistical Parametric Mapping… group 1group 2 voxel by voxel modelling –  parameter estimate standard error = statistic image or SPM

16. “Globals” for VBM Shape is really a multivariate concept Dependencies among volumes in different regions SPM is mass univariate Combining voxel-wise information with “global” integrated tissue volume provides a compromise Using either ANCOVA or proportional scaling (ii) is globally thicker, but locally thinner than (i) – either of these effects may be of interest to us.

17. Total Intracranial Volume (TIV/ICV) “Global” integrated tissue volume may be correlated with interesting regional effects Correcting for globals in this case may overly reduce sensitivity to local differences Total intracranial volume integrates GM, WM and CSF, or attempts to measure the skull-volume directly Not sensitive to global reduction of GM+WM (cancelled out by CSF expansion – skull is fixed!) Correcting for TIV in VBM statistics may give more powerful and/or more interpretable results See also Pell et al (2009) doi:10.1016/j.neuroimage.2008.02.050doi:10.1016/j.neuroimage.2008.02.050

18. Some Explanations of the Differences Thickening Thinning Folding Mis-classify Mis-register

19. Overview Voxel-Based Morphometry Segmentation Use segmentation routine for spatial normalisation Gaussian mixture model Intensity non-uniformity correction Deformed tissue probability maps Dartel Recap

20. Segmentation Segmentation in SPM8 also estimates a spatial transformation that can be used for spatially normalising images. It uses a generative model, which involves: Mixture of Gaussians (MOG) Bias Correction Component Warping (Non-linear Registration) Component

21. Extensions for New Segment of SPM8 Additional tissue classes Grey matter, white matter, CSF, skull, scalp. Multi-channel Segmentation More detailed nonlinear registration More robust initial affine registration Extra tissue class maps can be generated

22. Image Intensity Distributions (T1-weighted MRI)

23. Mixture of Gaussians (MOG) Classification is based on a Mixture of Gaussians model (MOG), which represents the intensity probability density by a number of Gaussian distributions. Image Intensity Frequency

24. Belonging Probabilities Belonging probabilities are assigned by normalising to one.

25. Non-Gaussian Intensity Distributions Multiple Gaussians per tissue class allow non-Gaussian intensity distributions to be modelled. E.g. accounting for partial volume effects

26. Modelling a Bias Field A bias field is modelled as a linear combination of basis functions. Corrupted image Corrected image Bias Field

27. Tissue Probability Maps for “New Segment” Includes additional non-brain tissue classes (bone, and soft tissue)

28. Deforming the Tissue Probability Maps *Tissue probability images are deformed so that they can be overlaid on top of the image to segment.

30. Optimisation The “best” parameters are those that maximise the log-probability. Optimisation involves finding them. Begin with starting estimates, and repeatedly change them so that the objective function decreases each time.

31. Steepest Descent Start Optimum Alternate between optimising different groups of parameters

32. Multi-spectral

33. Limitations of the current model Assumes that the brain consists of only the tissues modelled by the TPMs No spatial knowledge of lesions (stroke, tumours, etc) Prior probability model is based on relatively young and healthy brains Less accurate for subjects outside this population Needs reasonable quality images to work with No severe artefacts Good separation of intensities Reasonable initial alignment with TPMs.

34. Overview Morphometry Voxel-Based Morphometry Segmentation Dartel Flow field parameterisation Objective function Template creation Examples Recap

35. DARTEL Image Registration Uses fast approximations Deformation integrated using scaling and squaring Uses Levenberg-Marquardt optimiser Multi-grid matrix solver Matches GM with GM, WM with WM etc Diffeomorphic registration takes about 30 mins per image pair (121×145×121 images). Grey matter template warped to individual Individual scan

36. Evaluations of nonlinear registration algorithms

37. Displacements don’t add linearly Forward Inverse Composed Subtracted

38. DARTEL Parameterising the deformation φ (0) = Identity φ (1) = ∫ u ( φ (t) ) dt u is a velocity field Scaling and squaring is used to generate deformations. t=0 1

39. Scaling and squaring example

40. Forward and backward transforms

41. Registration objective function Simultaneously minimize the sum of: Matching Term Drives the matching of the images. Multinomial assumption Regularisation term A measure of deformation roughness Regularises the registration. A balance between the two terms.

42. Effect of Different Regularisation Terms

43. Simultaneous registration of GM to GM and WM to WM Grey matter White matter Grey matter White matter Grey matter White matter Grey matter White matter Grey matter White matter Template Subject 1 Subject 2 Subject 3 Subject 4

44. Template Initial Average After a few iterations Final template Iteratively generated from 471 subjects Began with rigidly aligned tissue probability maps Used an inverse consistent formulation

45. Grey matter average of 452 subjects – affine

46. Grey matter average of 471 subjects

47. Initial GM images

48. Warped GM images

49. 471 Subject Average

52. Subject 1

53. 471 Subject Average

54. Subject 2

55. 471 Subject Average

56. Subject 3

57. 471 Subject Average

58. Overview Voxel-Based Morphometry Segmentation Dartel Recap

59. SPM for group fMRI fMRI time-series Preprocessing spm T Image Group-wise statistics Spatially Normalised “Contrast” Image Spatially Normalised “Contrast” Image Spatially Normalised “Contrast” Image Preprocessing fMRI time-series

60. SPM for Anatomical MRI Anatomical MRI Preprocessing spm T Image Group-wise statistics Spatially Normalised Grey Matter Image Spatially Normalised Grey Matter Image Spatially Normalised Grey Matter Image Preprocessing Anatomical MRI

61. VBM Pre-processing in SPM8 Use New Segment for characterising intensity distributions of tissue classes, and writing out “imported” images that DARTEL can use. Run DARTEL to estimate all the deformations. DARTEL warping to generate smoothed, “modulated”, warped grey matter. Statistics.

62. New Segment Generate low resolution GM and WM images for each subject (“DARTEL imported”). Generate full resolution GM map for each subject.

63. Run DARTEL (create Templates) Simultaneously align “DARTEL imported” GM and WM for all subjects. Generates templates and parameterisations of relative shapes.

64. Normalise to MNI Space Use shape parameterisations to generate smoothed Jacobian scaled and spatially normalised GM images for each subject.

65. Some References Wright, McGuire, Poline, Travere, Murray, Frith, Frackowiak & Friston. A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 2(4):244-252 (1995). Ashburner & Friston. “Voxel-based morphometry-the methods”. Neuroimage 11(6):805-821, (2000). Mechelli et al. Voxel-based morphometry of the human brain… Current Medical Imaging Reviews 1(2) (2005). Ashburner & Friston. “Unified Segmentation”. NeuroImage 26:839-851, 2005. Ashburner. “A Fast Diffeomorphic Image Registration Algorithm”. NeuroImage 38:95-113 (2007). Ashburner & Friston. “Computing Average Shaped Tissue Probability Templates”. NeuroImage 45:333-341 (2009). Klein et al. Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. NeuroImage 46(3):786-802 (2009). Ashburner. “Computational Anatomy with the SPM software”. Magnetic Resonance Imaging 27(8):1163-1174 (2009). Ashburner & Klöppel. “Multivariate models of inter-subject anatomical variability”. NeuroImage 56(2):422-439 (2011).